Abstract: Armed oncolytic viruses are an emerging therapeutic strategy for many cancers. The parvoviruses are the smallest viruses currently being developed as oncotherapeutic agents, and are non-enveloped and extremely rugged, simplifying their production, purification and storage, as well as enhancing their tissue penetration properties. Rodent protoparvoviruses can infect human cells only if neoplastically transformed, and thus are intrinsically oncotropic - the rodent protoparvovirus H-1 is currently in Phase I/IIA clinical trials against glioblastomaandpancreaticcancer.Wehavedevelopedareplicating,butnon-propagating,parvoviralvector system, which can be packaged into tumor cell target-enhanced capsid selected in vitro. These dual transgene vectors express secreted, soluble versions of murine or human PD-1 (sPD-1), or an anti-CTLA-4 camelidnanobody,coordinatelywiththemurineco-stimulatorymoleculesCD80orCD48,torenderthetumor cellitselfaneffectiveantigenpresentingcell.Wewilltestthehypothesisthatthesecretedtransgeneproducts will effectively block the two major immune checkpoint pathways when secreted directly within the tumor microenvironment, potentially avoiding the side-effects associated with systemic administration of immune checkpointinhibitors.